Increasing evidence suggests that transcriptional dysregulation in Huntington's disease (HD) perturbs cellular function and compromises protective mechanisms ultimately leading to neuronal death. We have discovered novel interactions between the Huntington's disease protein (huntingtin) and transcriptional regulators and that medications acting on these regulators are highly effective in vitro and in vivo. These compounds have provided by far the largest single drug effects on ameliorating the phenotype of HD transgenic mice to date. This work has arisen from collaborations between our different laboratories and the proposed projects are designed to understand and explore the therapeutic potential in lid of these compounds, conventionally used as chemotherapeutic agents. Project 1 (Dimitri Krainc, PI) will explore the molecular interactions between hunting(in and transcriptional machinery and how these interactions might be affected by medications. Project II (Dr. Rajiv Ratan, PI) will study the downstream mechanisms of neuroprotection exerted by the medications as they relate to oxidative and apoptotic signaling. Project IlI (Dr. Robert Fen'ante, PI) will utilize HD transgenic mice to examine the effects of the chemotherapeutic medications on an in vivo HD phenotype and model Preclinical treatments that can be used in humans. Project IV (Dr. Jang-Ho Cha, PI) will examine the effects of huntingtin and the medications on chromatin remodeling in part utilizing cells and tissues from the other aims. Project V (Dr. Steven Hersch, PI) will perform early phase clinical trials of the medications in HD patients to pave the way for potential large-scale efficacy trials. The Gene Expression Core (Dr. Ruth Luthi-Carter, PI) will provide transcriptional readouts relevant for studies in each of the projects. Our program thus examines new classes of therapeutic agents for HD and encompasses molecular, genetic and cellular mechanisms, therapeutic discovery in transgenic mouse models, and translation to early clinical use in HD patients. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The three institutions involved insure that the program will exist in a highly supportive environment.